Chronic cocaine abuse arises as a result of persistent cocaine-induced adaptations in the function of neurons within mesolimbocortical brain reward circuits. An understanding of the molecular mechanisms by which cocaine alters the function of these neural circuits may lead to development of novel therapies for the treatment of cocaine addiction. The overall hypothesis of this proposal is that cocaine exerts long-lasting effects on behavior by inducing the transcription of new gene products in the nucleus accumbens (NAc) that change the excitability and/or synaptic connectivity of NAc neurons. We have shown that genetically manipulating the expression of the methyl-DNA binding protein MeCP2 in specific regions of the adult striatum modulates the ability of cocaine and the related psychostimulant amphetamine to induce addictive-like behaviors in rodents. Furthermore, we find that cocaine induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in parvalbumin (Pv)-positive fast-spiking GABAergic interneurons (FSIs) in the NAc. The objective of this proposal is to test the novel hypothesis that phosphorylation of MeCP2 in FSIs provides a mechanism to link cocaine exposure with transcription-dependent changes in striatal circuit function that limit the rewarding properties of cocaine. To address this hypothesis, in Aim 1 we will test the consequences of MeCP2 phosphorylation on the rewarding and reinforcing properties of cocaine by assessing cocaine self-administration (SA) in mice bearing a mutation knocked into the Mecp2 gene that changes Ser421 to Ala, rendering MeCP2 non-phosphorylatable at this site. In Aim 2 we will test the hypothesis that MeCP2 acts in FSIs in the NAc to limit cocaine SA. We will achieve this goal by stereotaxically injecting LoxP-conditional viruses into the NAc of adult mice from a transgenic strain that expresses the Cre recombinase in Pv-positive neurons. We will use these viruses to manipulate MeCP2 expression and phosphorylation in these cells as a means to alter FSI function and we will determine the effects of these manipulations on cocaine SA. Finally in Aim 3 we will test the hypothesis that pMeCP2 regulates a striatal plasticity that limits cocaine SA by modulating the inducibility of immediate-early genes in FSIs of the NAc. The outcome of our study will be the experimental demonstration of a specific circuit-based mechanism by which the chromatin regulatory protein MeCP2 limits cocaine reward. These studies promise to yield significant new insights into the neurobiological mechanisms that impact susceptibility to cocaine addiction.